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We recently introduced a thermodynamically based deracemization process, co-crystallization-induced spontaneous deracemization (CoISD). Following the successful development of the CoISD process, we aimed at improving both yield and deracemization and, consequently, the productivity of the process. As the process is based on co-crystallization of the target enantiomer combined with a racemization reaction of the undesired enantiomer, both reaction and crystallization kinetics and thermodynamics need to be considered for optimization. Taking previously published kinetic parameters into account, here we investigate the nature of the solvent, concentration of the racemizing agent, equivalent of the acid co-former, and temperature of the crystallization cell. The evaluation of each parameter allowed for improvement of the yield and/or deracemization, ultimately providing an optimized process with a yield of 73% of pure co-crystals for an overall deracemization of 80%, in parallel, highlighting the viability of recycling the remaining mother liquors.

In pharmaceutical industry, 50% of the marketed drug compounds contain a chiral center, essential to their functioning. Where one enantiomer has the desired pharmacological effect, the other might be inactive, equally active or have adverse effects. For this reason, development of enantiopure drugs is strongly recommended by regulation authorities to industries. The industrially most prominent way to enantiopure drugs still involves formation of a racemic compound, followed by a chemical or physical resolution. Such a resolution implies a maximum yield of 50%, as the unwanted enantiomer is discarded upon separation. However, if the compound is racemizable, in principle the unwanted enantiomer can be transformed into the desired one, leading to a so-called deracemization process, which finally can lead to a 100% maximum yield. Such processes exist for compounds that either are intermediates (Dynamic Kinetic resolution), can form salts (Crystallization Induced Diastereomer Transformation) or conglomerates (Viedma Ripening). However, there are still a considerable amount of racemizable molecules that don’t meet either criteria and therefore cannot be deracemized. In this work, the aim is to develop a novel tool within the library of deracemization techniques in order to touch a larger range of compounds, with the ultimate goal to develop a physical thermodynamic deracemization technique applicable to all racemizable compounds. To do so, crystal engineering and crystal growth tools are combined to develop a Co-crystallization Induced Spontaneous Deracemization method (CoISD). This process is based on co-crystallization in order to induce an imbalance in solution by precipitation of only one enantiomer while racemizing the excess of the other one in solution. Doing so, we first identified a suitable system on which to develop the CoISD process by synthetizing a series of analog compounds and submitting them to a co-crystal screening. A suitable co-crystal system composed, (SC - Sciences) -- UCL, 2020

The disclosure is directed to cocrystals of fasoracetam, including R-fasoracetam, and various coformers. Crystalline materials comprising fasoracetam, including R-fasoracetam, are also provided. The disclosure further includes pharmaceutical compositions and methods of treatment of the cocrystals and crystalline materials of the disclosure

Health expectancies are key indicators for monitoring the health of populations, as well as for informing debates about compression or expansion of morbidity. However, current methodologies for estimating them are not entirely satisfactory. They are either of limited applicability due to high data requirements (the multistate method) or based upon questionable assumptions (the Sullivan method). This paper proposes a new method, called the “intercensal” method, which relies on the multistate framework using widely available data. The method uses age-specific proportions “healthy” at two successive, independent cross-sectional health surveys, and, together with information on general mortality, solves for the set of transition probabilities that produces the observed sequence of proportions healthy. The system is solved by making realistic parametric assumptions about the age patterns of transition probabilities. Using data from the Health and Retirement Survey and from the National Health Interview Survey, the method is tested against both the multistate method and the Sullivan method. We conclude that the intercensal approach is a promising framework for the indirect estimation of health expectancies.